My overall career goal is to work in a university setting where I can pursue my research interests in the neurochemistry underlying addiction and relapse, potential interventions for addiction, and the behavioral consequences of addiction. The K99/R00 Pathways to Independence award is an important step in achieving this goal. The proposed award would allow me to achieve an independent career in academic research through mentoring, collaboration, research and new research skills, and grant writing. The University of Utah can provide the facilities and equipment, mentoring, and collaborative research environment to not only achieve the research proposed for the K99 award, but also launch my career as an independent investigator. The University of Utah has many prominent researchers in the field of methamphetamine (METH) toxicity that are committed to maximizing my potential as a researcher. My mentors, Dr. Fleckenstein and Hanson, have been instrumental in helping me achieve my postdoctoral career goal of enhancing my ability to study the neurochemical changes associated with drug addiction. The support provided by my mentors and mentoring committee (Drs. Bevins & Wilkins), and consultants (Drs. Yamamoto, LaLumiere, Keefe & Wilcox) will allow me to expand my research techniques by learning optogenetics and autoradiography, improve my grant writing and laboratory management skills, and enhance my abilities to teach and mentor future generations. The proposed research will allow me to expand beyond the scope of my mentors' research on the neurochemical effects METH self-administration (SA) in the striatum by investigating the role of neurochemical changes in the frontal cortex in METH SA and reinstatement. Since changes in the frontal cortex have been observed in human METH addicts and are implicated in the cognitive deficits associated with drug abuse, better understanding these changes are important for understanding addiction and relapse. This will be assessed by 1.) identifying the specific serotonergic changes that occur in the frontal cortex following METH SA; 2.) investigating the role of excitatory activity in the medial prefrontal cortex during the reinstatement of METH- seeking; 3.) investigating the role of serotonin and glutamate release and 5HT2A receptor stimulation in the medial prefrontal cortex during the reinstatement of METH-seeking; and 4.) investigating if sex differences in serotonergic function contribute to sex differences in METH-seeking. The current proposal will provide insight into the role of changes in the frontal cortex in the relapse of METH addiction and allow for the targeted development of potential therapeutics. It will also set the foundation to further investigate sex differences in drug abuse. In addition to conducting this important research, this grant will help enable me to submit an R03 grant to pilot data of the behavioral effects of the neurochemical changes following METH SA and R01 grant based on the findings of the proposed studies. The research proposed, in addition to the mentoring described, will enhance my potential to become a successful independent researcher investigating drug addiction.